Evolutionary/Adaptive Factors in Breast Cancer in African-Americans

非洲血统的妇女（AA）比欧洲血统的妇女（EA）更容易被诊断出来 45岁之前患有乳腺癌，并且具有更具侵袭性的肿瘤，其特征是阴性， 雌激素、孕激素和HER-2受体（三阴性）。年轻的AA妇女是两倍多， EA妇女可能被诊断为基底样乳腺肿瘤，一种预后不良的内在亚型。 这些种族差异的原因尚不清楚，现有的AA妇女的研究缺乏统计数据， 研究乳腺癌危险因素的能力，这些危险因素由早期发病年龄和肿瘤生物学定义。我们 假设非洲数千年进化导致了编码特定表型的遗传图谱， 例如抵抗地方性传染病强有力的炎症/免疫反应，以及较高的皮肤 黑色素含量，以保护免受紫外线辐射，但这些因素可能会增加侵袭性肿瘤的风险， 特别是在北方或更城市化的环境中。我们特别 假设早期侵袭性乳腺癌可能是由于炎症反应增强所致 这可能会增加致癌的促炎环境，和/或来自维生素D缺乏症，由于高 皮肤色素沉着使用来自AA中四项最大的乳腺癌研究的汇总资源 女性，我们将通过首先测量血清维生素D（25 OH-D）水平和30个小组来解决这些目标。 800名AA和800名EA对照之间的免疫/炎症标志物，通过血统进行比较，使用血统 信息标记。血清标志物和SNPs之间的关系以及流行病学因素将 被评价。我们将建立维生素D的预测模型并使用这些分数来评估关系 与乳腺癌亚组进行病例对照比较。最后，我们将评估同一组中的SNP 免疫炎症标志物和维生素D代谢以及与乳腺癌相关的信号通路 癌症亚组中的5,534例AA病例和5,534例对照的汇总数据。根据我们的结果，我们将 进行交叉项目旨在检查乳腺癌亚组之间的关联和相互作用 炎症途径、产次和母乳喂养之间的关系（项目2）;体型和维生素D途径 （项目3）;以及相关通路和炎症及维生素D通路中的遗传易感性等位基因 易感性标志物我们相信，我们新颖但生物学上合理的假设可能揭示风险因素， 对于早期的侵袭性癌症，可以采取行动进行预防。

Women of African ancestry (AA) are more likely than women of European ancestry (EA) to be diagnosed with breast cancer before age 45, and to have more aggressive tumors, characterized by negativity for estrogen, progesterone and HER-2 receptors (triple negative). Younger AA women are more than twice as likely as EA women to be diagnosed with basal-like breast tumors, an intrinsic subtype with poor prognosis. The reasons for these racial disparities are unclear, and existing studies of AA women lack the statistical power to investigate risk factors for breast cancer defined by early age at onset and tumor biology. We hypothesize that evolution over millennia in Africa resulted in genetic profiles encoding specific phenotypes, such as robust inflammatory/immune response to withstand endemic infectious disease, and higher skin melanin content to protect from UV radiation, but that these factors may increase risk of aggressive tumors, particularly in the context of life in the northern hemisphere or in a more urban environment. Specifically, we hypothesize that early onset aggressive breast cancer may result from enhanced inflammatory responses which can augment the carcinogenic pro-inflammatory milieu, and/or from vitamin D deficiency due to high skin pigmentation. Using the pooled resources from four of the largest studies of breast cancer in AA women, we will address these aims by first measuring serum levels of vitamin D (25OH-D) and a panel of 30 immune/inflammatory markers among 800 AA and 800 EA controls, comparing by ancestry, using ancestry Informative markers. Relationships between serum markers and SNPs, as well as epidemiologic factors will be evaluated. We will build a predictive model for vitamin D and use those scores to evaluate relationships with breast cancer subgroups in case-control comparisons. Finally, we will evaluate SNPs in the same panel of immune inflammatory markers and vitamin D metabolism and signaling pathways in relation to breast cancer subgroups in our pooled data of 5,534 AA cases and 5,534 controls. Using our results, we will conduct cross-Project aims to examine associations between breast cancer subgroups and interactions between inflammatory pathways, parity and breastfeeding (Project 2); body size and vitamin D pathways (Project 3); and genetic susceptibility alleles In relevant pathways and inflammatory and vitamin D pathway susceptibility markers. We believe that our novel, but biologically sound hypotheses may reveal risk factors for early, aggressive cancer that can be acted upon for prevention.